US 2012022.0962A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0220962 A1 HSU et al. (43) Pub. Date: Aug. 30, 2012 (54) TRANSIDERMAL AND TOPCAL ation-in-part of application No. 09/972,008, filed on ADMINISTRATION OF VITAMINS USING Oct. 4, 2001, now Pat. No. 6,582,724, which is a con BASC PERMEATION ENHANCERS tinuation-in-part of application No. 09/738,410, filed on Dec. 14, 2000, now Pat. No. 6,586,000, which is a (75) Inventors: Tsung-Min HSU, San Diego, CA continuation-in-part of application No. 09/738,395, (US); Nicole T. GRICENKO, San filed on Dec. 14, 2000, now Pat. No. 6,719,997, which Diego, CA (US); Alan T.J. is a continuation-in-part of application No. 09/607, HICKEY, San Diego, CA (US); 982, filed on Jun. 30, 2000, now abandoned, which is a Eric C. JACOBSON, San Diego, continuation-in-part of application No. 09/596,889, CA (US); Rose C. LOBELLO, San filed on Jun. 19, 2000, now Pat. No. 6,455,830, which Diego, CA (US); Jane OBARA, is a continuation-in-part of application No. 09/465, San Diego, CA (US) 098, filed on Dec. 16, 1999, now abandoned. (73) Assignee: TECHNOLOGY RECOVERY Publication Classification SYSTEMS, LLC, (51) Int. C. MINNEAPOLIS, MN (US) A6M 35/00 (2006.01) (21) Appl. No.: 13/468,821 (52) U.S. Cl. ......................................... 604/307; 604/304 (22) Filed: May 10, 2012 (57) ABSTRACT Methods are provided for enhancing the permeability of skin Related U.S. Application Data or mucosal tissue to topical or transdermal application of (60) Continuation of application No. 12/343,000, filed on pharmacologically or cosmeceutically active agents. The Dec. 23, 2008, which is a continuation of application methods entail the use of a base in order to increase the flux of No. 10/860,887, filed on Jun. 3, 2004, now abandoned, the active agent through a body Surface while minimizing the which is a division of application No. 10/177,436, filed organic base. Compositions and transdermal systems are also on Jun. 20, 2002, now abandoned, which is a continu described. US 2012/O220962 A1 Aug. 30, 2012 TRANSIDERMAL AND TOPCAL through the skin. As will be appreciated by those in the field, ADMINISTRATION OF VITAMINS USING chemical enhancers are compounds that are administered BASIC PERMEATION ENHANCERS along with the drug (or in some cases the skin may be pre treated with a chemical enhancer) in order to increase the CROSS-REFERENCE TO RELATED permeability of the stratum corneum, and thereby provide for APPLICATIONS enhanced penetration of the drug through the skin. Ideally, Such chemical penetration enhancers or “permeation enhanc 0001. This application is a continuation of U.S. Ser. No. ers, as the compounds are referred to herein, are compounds 12/343,000 filed on Dec. 23, 2008. U.S. Ser. No. 12/343,000 that are innocuous and serve merely to facilitate diffusion of is a continuation of Ser. No. 10/860,887, filed on Jun. 3, 2004. the drug through the stratum corneum. The permeability of Ser. No. 10/860,887 is a divisional of U.S. Ser. No. 10/177, many therapeutic agents with diverse physicochemical char 436 filed on Jun. 20, 2002. U.S. Ser. No. 10/177,436 is a acteristics may be enhanced using these chemical enhance continuation in part of U.S. Ser. No. 09/972,008 filed on Oct. ment means. However, there are skin irritation and sensitiza 4, 2001 and now issued as U.S. Pat. No. 6,582,724, which is tion problems associated with high levels of certain a continuation in part of U.S. Ser. No. 09/738.410 filed on enhancers. Dec. 14, 2000 and now issued as U.S. Pat. No. 6,586,000, 0006. Accordingly, although there are many chemical which is a continuation in part of U.S. Ser. No. 09/569,889 methods of enhancing permeation, there remains an ongoing filed on May 11, 2000 and now abandoned, which is a con need for a method that is highly effective in increasing the rate tinuation in part of U.S. Ser. No. 09/465,098 filed on Dec. 16, at which a drug permeates the skin, does not result in skin 1999 and now abandoned; and is a continuation in part of U.S. damage, irritation, sensitization, or the like, and can be used Ser. No. 09/738,395 filed on Dec. 14, 2000, which is a con to effect transdermal delivery of even high molecular weight tinuation in part of U.S. Ser. No. 09/607,892 filed on Jun. 30, drugs such as peptides, proteins, and nucleic acids. It has now 2000, now abandoned, the disclosures of which are incorpo been discovered that basic permeation enhancers as described rated herein by reference. hereinare highly effective permeation enhancers, and provide FIELD OF THE INVENTION all of the aforementioned advantages relative to known per meation enhancers. Furthermore, in contrast to many conven 0002 This invention relates generally to the topical and tional enhancers, transdermal administration of drugs with transdermal administration of pharmacologically or cosme basic permeation enhancers, employed at the appropriate lev ceutically active agents, and more particularly relates to els, does not result in Systemic toxicity. methods and compositions for enhancing the flux of pharma cologically active agents through a body Surface by treatment SUMMARY OF THE INVENTION with a basic permeation enhancer. 0007. One aspect of the invention pertains to a method for enhancing the flux of a drug through a body Surface, compris BACKGROUND OF THE INVENTION ing: (a) administering the drug to a localized region of a 0003. The delivery of drugs through the skin provides human patient's body Surface; and (b) administering a basic many advantages; primarily, such a means of delivery is a permeation enhancer to the localized region, the enhancer comfortable, convenient and noninvasive way of administer comprising a pharmaceutically acceptable base and being ing drugs. The variable rates of absorption and metabolism present in an amount effective to provide a pH within the encountered in oral treatment are avoided, and other inherent range of about 8.0-13.0 at the localized region of the body inconveniences, e.g., gastrointestinal irritation and the like, Surface during administration of the drug and to enhance the are eliminated as well. Transdermal drug delivery also makes flux of the drug through the body Surface without causing possible a high degree of control over blood concentrations of damage thereto. The pharmaceutically acceptable base can be any particular drug. an inorganic or an organic base. 0004 Skin is a structurally complex, relatively thick mem 0008 Another aspect of the invention relates to a compo brane. Molecules moving from the environment into and sition for the enhanced delivery of a drug through a body through intact skin must first penetrate the stratum corneum Surface, comprising a formulation of: (a) a therapeutically and any material on its surface. They must then penetrate the effective amount of the drug; (b) a pharmaceutically accept viable epidermis, the papillary dermis, and the capillary walls able base, in an amount effective to provide a pH within the into the blood stream or lymph channels. To be so absorbed, range of about 8.0-13.0 at the body surface during adminis molecules must overcome a different resistance to penetra tration of the drug and to enhance the flux of the drug through tion in each type of tissue. Transport across the skin mem the body Surface without causing damage thereto; and (c) a brane is thus a complex phenomenon. However, it is the cells pharmaceutically acceptable carrier Suitable for topical or of the stratum corneum, which present the primary barrier to transdermal drug administration. In one aspect of the inven absorption of topical compositions or transdermally admin tion the pH is about 8.0-11.5 and in another aspect, the pH is istered drugs. The stratum corneum is a thin layer of dense, about 8.5-10.5. The formulation is typically aqueous. The highly keratinized cells approximately 10-15 microns thick pharmaceutically acceptable base can be an inorganic or an over most of the body. It is believed to be the high degree of organic base. keratinization within these cells as well as their dense packing 0009. Yet another aspect of the invention pertains to a which creates in most cases a Substantially impermeable bar system for the enhanced topical or transdermal administra rier to drug penetration. With many drugs, the rate of perme tion of a drug, comprising: (a) at least one drug reservoir ation through the skin is extremely low without the use of containing the drug and a pharmaceutically acceptable base, Some means to enhance the permeability of the skin. in an amount effective to enhance the flux of the drug through 0005 Numerous chemical agents have been studied as a the body Surface without causing damage thereto; (b) a means means of increasing the rate at which a drug penetrates for maintaining the system in drug and base transmitting US 2012/O220962 A1 Aug. 30, 2012 relationship to the body Surface and forming a body Surface polyurethane, a polyvinyl alcohol, a polyacrylic acid, a poly system interface; and (c) a backing layer that serves as the oxyethylene, a polyvinylpyrrolidone, a poly(hydroxyethyl outer surface of the device during use, wherein the base is methacrylate) (poly(HEMA)), or a copolymer or mixture effective to provide a pH within the range of about 8.0-13.0 at thereof.